Antibiotic resistance is a worldwide problem with catastrophic potential. The American Society of Microbiology Task Force recently issued a report defining the resistance problem and calling for new antibacterial agents with novel structures or mechanisms to offer alternatives to existing therapeutic choices (Southern Med. J., 1995; 88:797).
The quinolones are a class of antibacterials that are widely used throughout the world. The quinolones are potent inhibitors of gram positive and gram negative bacteria, and may be administered orally or intravenously. The quinolones are routinely used even though they have side effects (J. Antimicrob. Chemother., 1994; 33:685), and significant resistance has been frequently noted (Gootz, Medicinal Research, 1996; Rev. 16:433). One of the most widely used quinolones is ciprofloxacin, which has the following chemical structure:

The quinolones have a distinct structure activity relationship (SAR) which is defined by several thousands of analogs prepared over the last 30 years (S. Mitsuhashi, ed. Progress in Drug Research, 1992; 38:11-147). In the quinolone SAR (referring to the formula below representing substituted quinolones), it is well-established that the N1 group, in combination with the C3-carboxyl and the C4-carbonyl, are essential for activity, and that any substituents at C2 detract from activity (J. Antimicrob. Chemother., 1994; 33:685 and Gootz, supra., 1996). It is also well-established that R6 is ideally fluorine, and that R7 is a nitrogen containing heterocycle. R1 is ideally a small alkyl, a cycloalkyl, or a phenyl group.

The quinolones inhibit bacterial growth by inhibition of DNA gyrase and topoisomerase IV (Gootz, supra., 1996). The gyrase interaction appears to rely on the N1/C4-carbonyl/C3-carboxyl relationship.
Attempts to design novel quinolone mimics have focused on the N1/C4-carbonyl/C3-carboxyl relationship. Certain tricyclic isothiazole analogs were designed to keep an all-planar relationship, and to have the NH of the isothiazole ring be as acidic as the quinolone C3-carboxyl group (Chu, Drugs Exptl. Clin. Res., 1990; 16:215).
While maintaining excellent antibacterial activity, these compounds also show antitumor and mammalian topoisomerase activity (Drugs of the Future, 1992; 17:1101). These activities are undesired in an antibacterial agent.
Several publications (U.S. Pat. No. 5,283,248; J. Med. Chem., 1992; 35:1358; Antimicrob. Agents Chemother., 1995; 39:163) disclose tricyclic compounds (such as the structure below) having antibacterial activity and DNA gyrase inhibiting activity.
For such compounds, the relationship of the N1 to the C4-carbonyl is skewed. Compounds of this type are ineffective against bacteria that are quinolone resistant.
Other tricyclic analogs of the following structure are disclosed as quinolone mimics (JP 4,091,090 3/92; Interscience Conference on Antimicrobial Agents and Chemotherapy 1991, Abstract 1494).
While the ideal quinolone N1—C4-carbonyl relationship is maintained, the C2 region, where substitution is undesirable, is part of a fused-ringed system. These compounds are not active against quinolone resistant bacteria.
WO 96/04288 describes a series of benzoheterocycles of the formulas
where X, Y, and Z are hydrogen bond acceptor and donator groups. Among the compounds depicted are N-hydroxy-quinazoline-2,4-diones, where R1-R4 can represent hydroxy, amino, nitro, a variety of alkyls, esters, and amides. In all cases, the substituent on N1 is hydrogen. None of the substituents R1-R4 are nitrogen containing heterocycles. No antibacterial activity is disclosed for these compounds.
U.S. Pat. No. 5,155,110 describes N1-aryl-N-hydroxy-quinazoline-2,4-diones of the formula
where R may be halo, cyano, hydroxy, alkoxy, and substituted amino. Amino heterocycles are not included in R, and no antibacterial activity is reported for such compounds.
Compounds taught in International Publication No. WO 95/19346 as AMPA, NMDA, and kinase receptor antagonists have the formula
where R substituents are defined as alkyl or phenyl, and R1 and R2 are defined as H, alkyl, alkoxy, alkenyl, halogen, NO2, (un)substituted NH2, CN, etc. Again, no antibacterial activity is disclosed for these compounds.
Kornet and coworkers (Kornet M. J. et al., J. Heterocyl. Chem., 1984; 21:1533-1535) disclosed anticonvulsant compounds having the formula
where R is defined as H, Me, or Cl; R1 and R2 as H or Me; and R3 as Me or t-butyl. Alternatively, R2 and R3, together with the nitrogen atom to which they are attached, can form a heterocyclic ring such as piperidinyl, morpholinyl, etc. These compounds are not reported to have antibacterial activity.
A number of publications teach compounds having diuretic and sedative activities and with the generic structure as follows (ES 80/489675, JP 80/33323, BE 80/199792, FR 78/33438, JP 70/97932; Baronnet R., Callendret R., Blanchard L., Foussard-Blanpin O., Bretaudeau J., Eur. J. Med.-Chim. Ther., 1983; 18:241-247).
These are compounds in which NR1R2 can form a heterocycle, or R1 and R2 independently can represent H or a small alkyl. R3 and R4 can represent H, halogen, sulphonamide, alkyl, or alkoxy. No antibacterial activity is reported for these compounds.
International Publication No. WO 99/21840 describes 3-hydroxy-quinazoline-2,4-diones as antibacterial agents.
Compounds of this type are quinolone mimics where the 3-position exocyclic carboxylic acid of the quinolones is replaced by an oxo at the 2-position and a hydroxy at the N-3-position. Compounds of this type are designed to keep an all-planar relationship and to have the N—OH remain acidic, as in the quinolone CO2H (Chu, Drugs Exptl. Clin. Res., 1990; 16:215). These compounds inhibit DNA gyrase and topoisomerase IV, and demonstrate antibacterial activity in vitro. However, such compounds are not effective against quinolone resistant bacteria.
The need continues to find new antibacterial agents that have the potency of the quinolones, but which are active against quinolone resistant bacterial strains. The present invention provides such compounds, which are characterized as 3-aminoquinazolin-2,4-diones. An object of this invention is to provide these new compounds, and a method for treating bacterial infections in mammals by administering these compounds.